WO2009007991A2

WO2009007991A2 - A new process for preparation of atovaquone and novel intermediates thereof

Info

Publication number: WO2009007991A2
Application number: PCT/IN2008/000251
Authority: WO
Inventors: Ashok Kumar; Suneel Yeshwant Dike; Pramilkumar Mathur; Byju Thenkachen Nellithanath; Brajesh Sharma; Swapnil Shreekant Kore; Vitthal Suryabhan Buchude
Original assignee: Ipca Laboratories Limited
Priority date: 2007-04-19
Filing date: 2008-04-17
Publication date: 2009-01-15
Also published as: US7847127B2; WO2009007991A3; US20100081847A1

Abstract

Disclosed herein is novel process for preparation of Atovaquone, which process includes reacting 1,4-naphthoquinone with trans-4-(4-chlorophenyl) cyclohexane carboxylic acid followed by halogenation to obtain dihalo-compound, further dehydrohalogenation of dihalo- compound to obtain monohalogeno-compound, and hydrolysis of the monohalogeno - compound to obtain Atovaquone. The invention further discloses Atovaquone in a substantially pure and well defined polymorphic form designated as 'Form IPCA-ATO', and the preparation thereof.

Description

A new process for preparation of Atovaquone and novel intermediates thereof.

Technical field of invention:

The present invention relates to a new process for preparation of Atovaquone. In particular, the present invention relates to novel intermediates useful in the preparation of Atovaquone and obtainment of Atovaquone in novel polymorphic form. More particularly, invention relates to an advantageous crystalline form, that has improved solubility and other bulk characteristics suitable for pharmaceutical application. The present invention also relates to processes for preparing such crystalline form of Atovaquone and its use in industry. Atovaquone is a useful medicine for the treatment and prophylaxis of Pneomcystis carinii infections.

Background of invention:

Atovaquone, chemical name being ;ra«5-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy- 1 ,4-naphthoquinone, is & hydroxy- 1 ,4-naphtoquinone, an analog of ubiquinone, with antipneumocystic activity. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Due to its inhibitory effect in sensitive parasites, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis, thus has got great pharmaceutical interest/importance.

Atovaquone is the trans-isomer of 2-[4-(4-chlorophenyl)cyclohexyI]-3-hydroxy-l ,4- naphthoquinone whose synthesis, activity and uses are disclosed in the patent Nos. US5053432 and EP0362996.

There are only few reports available for the preparation of Atovaquone exploring various synthetic alternatives., and is mainly based on a decarboxylative condensation process, as shown in scheme 1 , that is practically used in these disclosures. These methods are analogous to the methods disclosed in Journal of American Chem. Society, 1948, yielding the condensation product in nearly 1 to 6% only [F. Fieser, J. American Chemical Society, vol. 70, 3174-3180 (1948)]. As reported, the production yield of Atovaquone using process of '432 patent is very poor, practically in the range of 3-5% only.

Atovaquone Formula I

Scheme 1

Thus a search for a manufacturing process for the preparation of Atovaquone resulting in a satisfactory yield / purity of final product remains undoubtedly of interest.

Apart from this, there is a great challenge in obtainment of Atovoquone of better solubility and dissolution characteristics. However, there is only single report on the production of different crystalline form of Atovaquone, as disclosed in WO2006008752. The '752 publication discloses that Atovaquone can exist in three different polymorphic forms (designated as Form I and Form II and Form III) and provided analytical characterization for those polymorphs. The product obtained by the basic molecule patent was characterized for the first time in this publication, and designated as Form I. The stability data of the reported forms are not reported. However, it is important to note the reports on micro-particles of Atovaquone, for example US6018080 & US6649659 disclose such micro-particles and processes for producing the same. These patents clearly identify the product manufactured by the process of US5053432, meaning the crystalline form I, is poorly bio-available. The microparticles of Atovaquone, prepared by a complicated process have been ascribed to have increased bioavailability. It has been narrated that the US5053432 process yielded macroparticles of Atovaquone, and is not suitable to be administered as such or even by conventional milling, due to poor solubility of the crystals in common organic/aqueous solvents. Therefore, there is a need in the art to search new forms of Atovaquone, which are having better solubility and improved bioavailability for making suitable dosage forms for pharmaceutical application.

Therefore the object of this invention is to develop alternative processes for the synthesis of Atovaquone, more specifically in its trans isomer form with improved physical properties.

Summary of the invention:

The present inventors had discovered that the prior art processes present substantial difficulties in producing Atovaquone in a consistent and reliable manner in satisfactory yields. The invention, therefore, aims to provide a new process for making Atovaquone. In accordance with one aspect, the invention provides a process for preparation of Atovaquone, which process includes reacting 1,4-naphthoquinone with trans-4-(4- chlorophenyl)cyclohexane carboxylic acid followed by chlorination, dehydrohalogenation, and hydrolysis according to scheme 2.

Scheme 2 The intermediate compound of formula III and substantially pure trans-form of compound of Formula Il are novel, which form part of the present invention and sought patent protection.

It has been seen that the crystalline forms disclosed in the prior art are substantially coarser crystals and the solubility of those forms are found to be very poor. It has now surprisingly been found that the Atovaquone crystals can occur in a structurally different physical form. In a second aspect, the present invention provides Atovaquone in a substantially pure polymorphic form, hereinafter referred to as the compound of the invention. The novel polymorph of Atovaquone can be obtained as a well defined compound and is herein after designated as "Form IPCA-ATO". The character of the new form can be defined either by distinct peaks in powder X-Ray pattern, distinct endotherms in DSC or peaks in IR spectrum.

The present invention also provides suitable process to obtain and a method of differentiating the novel form of Atovaquone from other forms of Atovaquone. The compound of the invention is advantageous because it is found to be stable with lower bulk density than the corresponding morphologically different Atovaquone compounds in prior art and is therefore appear to have better solubility properties leading to higher bioavailability. The compound of the invention is also easier to characterize because it exists in a well defined state. The compounds are useful for pharmaceutical application with improved properties/adaptability and thus the invention includes pharmaceutical compositions containing the compound of the present invention.

Brief Description of the Drawings:

Fig.l shows an X-Ray Powder Diffractogram of an exemplary batch of "Form IPCA-

ATO" of Atovaquone obtained in accordance with the invention.

Fig 2. shows Infra -Red spectra of "Form IPCA-ATO" of Atovaquone obtained in accordance with the invention.

Fig.3 shows a Differential Scanning calorimetry analysis diagram of an exemplary batch of "Form IPCA-ATO" of Atovaquone obtained in accordance with the invention Detailed description of the invention:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.

The term "isolating" is used to indicate separation or collection or recovery of the compound of the invention being isolated in the specified form. The term "separating from a solvent" with respect to the solids described herein means obtaining a solid of specified characteristics from a solution or a partial solution.

The term "treating" means adding or combining or mixing the stated reagent or materials to the things being treated. The term "forming a solution" means obtaining a solution of a substance in a solvent in any manner. It encompasses partial solutions. The term 'stable' as used herein, refers to the tendency to remain substantially in the same physical form for at least a month, preferably at least 6 months, more preferably at least a year, still more preferably at least 2 years, when stored under ambient conditions (20 °C/60% RH) without external treatment. Substantially the same physical form in this context means that at least 50%, preferably at least 80% and more preferably at least 90% of the crystalline form remains.

For the purposes of this description and claims of the present invention, the phrase "Atovaquone 'Form IPCA-ATO' refers to the novel form of Atovaquone, wherein the 'IPCA-ATO', is referring to a crystalline form of Atovaquone that one of skill in the art can identify as a distinct entity distinguishable from other crystalline forms of Atovaquone based on the characterization details provided herein with the present invention. As used herein, the phrase having "at least one characteristic of "Form IPCA- ATO" ', refers to a crystalline form of Atovaquone that possesses at least one of the characteristic PXRD peaks or distinct peaks in Infra Red spectrum provided herein. For example, a single or a combination of PXRD peaks which are not found in another crystalline form of Atovaquone is enough to show at least one of the characteristics of "Form IPCA-ATO" of Atovaquone, the compound of the present invention. A single or a combination of peaks in an FT IR spectrum provided herein with this invention may also serve the same purpose.

Identification of solids obtained by the present invention can be made by methods known in the art per se such as X-Ray powder diffraction, Fourier Transform Infrared (FT-IR) spectra and of course, it should be understood that operator, instrument and other similar changes may result in some margin of error with respect to analytical characterization of the solid.

The FTIR, DSC and XRPD methods used for the identification and characterization of the novel form of Atovaquone are described below:

a) FT-IR spectral analysis

FTIR spectra of novel form was recorded directly on untreated powder by means of spectrometer. Spectra was recorded at room temperature from 4000 cm-1 to 650 cm- 1, for each sample 32 scans were collected at a resolution of 4 cm-1. b) X-ray powder diffraction studies.

Analytical characterization of the compound according to the invention was carried out by using X-ray powder diffraction using a PANalytical XpertPRO X-Ray machine of Philips make. The X-ray powder diffraction patterns were recorded with Cu K alpha-1 radiation source (voltage of 45 kV; current: 40 mA).. The step scan mode was performed with a step size of 0.008 °, at a scan rate of 14.59 step/s c) Differential Scanning Calroimetry (Abbreviated as DSC).

Differential scanning calorimetry analysis of the novel form was recorded at a heating rate of 10 ⁰C per minute at a temperature range from 50 ⁰C to 250 ⁰C.

"Atovaquone" is a free species of /rørø^-^-chlorophenyO-cyclohexyO-S-hydroxy-l ^- naphthoquinone, which has the trans geometry. It has the following formula:

Atovaquone Formula I

The inventors of the present invention had found that the use of 2-chloro-l,4- naphthoquinone in the condensation reaction with /rørø-4-(4-chlorophenyl)cyclohexane carboxylic acid does not provide a reliable, consistent methodology to prepare atovaquone due to poor selectivity, and yield reaches only in the range of 3-5%. The intermediate trans-isomer of compound of Formula IV (scheme 1 ), according to reported processes, is obtained in only 5-7% yield, and that too is present in a large junk of impurities and its corresponding c/s-isomer (Formula IV-cw-geometry) making it difficult to purify. The present inventors, on exploring various process alternatives, for a reliable process solution have found that the use of unsubstituted 1 ,4-naphthoquinone in the condensation reaction provides a significantly better yield in the condensation reaction and permits reliable isolation of trans-isomer, which can be further converted to Atovaquone. The process of the present invention is represented in scheme 2 given before.

Thus, according to the present invention, there is provided a process for preparation of Atovaquone, said process comprises the steps of a) reacting the 1 ,4-naphthoquonone with 4-(4-chlorophenyl)cyclohexane carboxylic acid to obtain the compound of Formula 11; b) halogenating compound of formula II to form a dihalo-compound of formula III; c) Subjecting compound of formula III to dehydrohalogenation reaction to obtain a compound of formula IV; and d) Converting the monohalogeno-compound of formula IV into Atovaquone .

In the process step (a), 4-(4-chlorophenyl)cyclohexane carboxylic acid used is preferably in trans-isomer form. The reaction is conducted in presence of a metal nitrate and a persulphate reagent, preferably the metal nitrate is silver nitrate and the persulphate reagent is ammonium persulphate. The reaction step (a) may be performed in an aqueous and/or organic solvent. The solvent for the reaction can be chosen from any inert solvent, preferably selected from polar protic and polar aprotic solvent. The aqueous solvent is water or water containing organic solvents. Preferably it is a mixture of water and acetonitrile. The reaction can be carried out optionally in presence of a catalyst, for example, a metal iodide or a phase-transfer catalyst.

As the phase transfer catalyst, mention can be made of, for example, alogen, quaternary ammonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl group having 1 -18 carbon atoms, phenyl lower alkyl group and phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms such as tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as 1 -dodecanylpyridinium chloride and the like.

Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched chain alkyl group having 1 -18 carbon atoms such as tetrabutylammonium bromide or alogen are particularly preferred.

The reaction is carried out usually at a temperature not lower than ambient temperature and between the reflux temperature of the solvent, and preferably at a temperature of 50-

1 10[deg.] C. The reaction time is usually from about 1 hour to about 10 hours.

It is recommended to use the naphthoquinone in excess, usually in an amount of about 1.1 to 2 mol per mol of the 4-(4-chlorophenyl)cyclohexane carboxylic acid. Also to use the silver nitrate usually in an amount of 0.1 to 0.9 moles, preferably 0.2 to 0.5 moles and persulphate reagent in an amount of 1.5 to 5 moles, preferably 1.5 to 2.5 mol per mol of 4-(4-chlorophenyl)cyclohexane carboxylic acid, respectively. And to use, optionally, the phase transfer catalyst usually in an amount of 0.1-1 mol and preferably 0.1 -0.25 mol per mol of the naphthoquinone, and to use the metal iodide in an amount of 0.1 to 1.0 mole and preferably in 0.1 to 0.3 mole per mol of the naphthoquinone.

The compound of formula (II) formed during the above-mentioned reaction can easily be isolated by the conventional separating means. As said separating means, mention can be made of, for example, distillation of solvent and excess reactants followed by crystallization, extraction method using a solvent, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. After the completion of reaction step (a), preferably the product of formula 11 is isolated in its trans-form and further used in the step b) conversion process. In the process of step b), the halogenation reaction of product of formula II is carried out in presence of a suitable halogenating agent, preferably the halogen is chlorine. Preferably chlorination is carried out by passing chlorine gas in presence of compound of formula II in glacial acetic acid or in any conventional solvent to obtain compound of formula III. In step c), the dehydrohalogenation of compound III is carried out by treatment of it with an acid or base in a suitable medium. Preferably, dehydrohalogenation is carried out by treating it with sodium acetate in glacial acetic acid to obtain compound of formula IV. The hydrolysis of compound of formula IV into atovaquone is carried out in a conventional manner by reacting it with a base like potassium hydroxide or sodium hydroxide in a solvent, which is preferably an alcohol.

The invention provides better yield of compound of formula II in the condensation reaction in the order of about 20-22% isolated yield. Thus the yield of the required tram- isomer is improved to a great extent by the practice of the present invention. The isolated compound of formula II in substantially pure trans-form is not made available in literature and also forms part of the present invention.

In a second aspect, the present invention provides Atovaquone in a substantially pure polymorphic form, hereinafter referred to as new compound of the invention. The compound of the invention is characterized by the positions of the major peaks in the X- ray powder diffractogram, but may also be characterized by conventional FT-IR spectroscopy and endotherms in DSC diagram. These characteristics are not exhibited by any other form of Atovaquone and accordingly, the "Form IPCA-ATO" of the present invention is easily distinguishable from any other crystal form of the Atovaquone disclosed in prior art.

Thus, the character of this new form ("Form IPCA-ATO") is confirmed either by PXRD patterns, DSC endotherms and FT IR spectra obtained from a sample thereof which are provided as Figures 1 to 3 respectively. The PXRD pattern shows at least one characteristic and exclusive peak at about 6.66 & 10.05 ±0.2 degrees 2 theta angles. More particularly the PXRD pattern shows characteristic and exclusive peaks at 6.66, 9.96, 13.1 1, 18.22, and 23.10 ±0.2 degrees 20 angles.

The novel form of Atovaquone "Form IPCA-ATO" is further characterized by FT-IR spectra having peaks at 3369, 2935, J 633, 1383, 1338, 1312, 123 land 1053 cm-1 , which are characteristic for the present form.

The novel form of Atovaquone "Form IPCA-ATO" is further characterized by endotherms in a DSC. Thermal analysis results in a Differential Scanning calorimeter thermogram taken at a heating rate of 10 degree Celsius per minute in a open pan that exhibits a melting endotherm with a peak temperature of about 1 17-130 ⁰C (an onset temperature in the range of of about 100-120 ⁰C), and a second endotherm having peak at about 220-222 ⁰C (onset temperature in the range of about 217-219). The position of the first endotherm can shift the position depending upon the heating rate and any contaminations resulting there from.

The main peaks, with positions and relative intensities, have been extracted from the diffractogram in FlG. 1 and are given below in table 1. The relative intensities are less reliable and some additional very weak peaks found in the diffractogram have been omitted from table 1. Table 1

In a further aspect, the present invention provides processes for the preparation of the Atovaquone "Form IPCA-ATO" which comprises; i) contacting Atovaquone of any physical form in an organic solvent to obtain a solution at a suitable temperature for a suitable time; ii) subjecting it to rapid chilling; and recovering the novel form from the reaction solution.

In one embodiment of the present invention, preparation of "Form IPCA-ATO" comprises i) subjecting a solution of Atovaquone to chilling either in a cold bath of liquid nitrogen or dry ice bath prepared in a suitable solvent medium until frozen and removing the solvent from the mass thus obtained to recover the new crystals of Atovaquone. Alternately the atovaquone solution may be added to either liquid nitrogen or dry ice to precipitate the new form followed by removing the solvent. The solvent may be removed under vacuum, preferably in a lyophilizer. The organic solvents may be selected from, but not limited to, chlorinated solvent, especially dichloromethane.

By a suitable temperature is meant a temperature which the solution can be formed and be able to induce the transformation of atovaquone into the novel form. Examples of such suitable temperatures include, but are not limited to, room temperature, preferably lower than room temperature, still preferably less than 0⁰C and more preferably less than minus 30 ⁰C. By a suitable time is meant a time that results in better conversion of the starting material into novel crystalline form without causing any decomposition of either compounds, i.e. results in a good yield. This suitable time will vary depending on the mode of chilling used, can be established by routine experimentation. The faster the rate of cooling, the shorter time is needed to give the desired conversion. The amount of solvent is not crucial and will depend on the process conversion & conditions desired. To have complete conversion to the novel form of the present invention, complete dissolution of Atovaquone in the selected solvent is desired. The process conditions are further illustrated in the Examples.

Atovaquone has been indicated for use in the following indications: Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. It may be used alone or concomitantly with other classes of agents like mefloquine or proguanil (Anti-malarials) .

In a further aspect the invention thus provides new compound which is Atovaquone "Form IPCA-ATO" for use in treating Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii, either alone or in combination with other antimalarial agents. In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of Atovaquone "Form IPCA-ATO" in any given case will depend on the nature and severity of the disease to be treated. The dose, dose frequency may also vary according to the age, body weight and response of the individual patient.

The invention thus provides pharmaceutical compositions containing Atovaquone "Form IPCA-ATO" which may optionally contain other crystalline forms and/or other active pharmaceutical drugs. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention can contain one or more commonly used pharmaceutical excipients. Excipients are added to the composition for a variety of purposes.

The bulk density of the new form was compared with the crystalline forms and found that the new form is lighter than other forms, the results are summarized in the below table.

The following examples are presented to illustrate the working of the present invention, but are not limiting the scope of the individual embodiments presented.

Example 1.

Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]- 1,4-naphthoquinone (Formula II) To a stirred solution of Silver nitrate 17.5 gm (0.104 moles ) dissolved in 100 ml water, 50 gm (0.209 moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid was added. To this solution acetonitrile 250 ml was added and under stirring heated to reflux and 33.1 gm (0.209 moles) 1,4-naphthoquinone was added. 120 gm (0.525 mole) Ammonium persulfate dissolved in 400 ml water was added drop-wise to the stirred solution and continued reflux for 2 hours. The reaction solution then cooled to 0-5 degree Celsius and extracted with methylene chloride. The organic layer was first washed with water followed by washing with 10% sodium carbonate aqueous solution, further with water till the pH is neutral. The organic layer was distilled to eliminate methylene chloride and was stirred in acetonitrile and filtered. The solid obtained was crystallized from acetonitrile to obtain 15 gm (20% yield). M.P. 146-149 (uncorrected), ¹H NMR (400MHz), δH (d₆- CDC13) 8.07-8.14(2H, m, Naphth), 7.65-7.74(2H, m, Naphth), 7.27-7.30(2H, d, arom.), 7.07-7.19 (2H, d, arom.), 6.80(1 H, s, naphtho.), 2.98-3.01 ( I H, tt, CH), 2.54-2.58(1 H, tt, CH-), 1.25-2.03(8H, multi, CH₂)

Example 2.

Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro- 1 ,4- naphthoquinone (Formula III)

10 gm of compound of formula II 2-[4-(4-chlorophenyl)cyclohexyl]- 1 ,4-naphthoquinone was added to 50 ml glacial acetic acid and to this solution chlorine gas was passed at about 20 degrees. The reaction mass was then quenched into water and filtered. The product was dried at 30 degree to obtain 1 1.5 gm (95% yield) compound of formula III. ¹ H NMR (400MHz), δH (d₆-CDC13) 8.13(2H, m, Naphth), 7.82-7.89(2H, m, Naphth), 7.0-7.30(4H, m, arom.), 4.90-5.0(1 H), 2.67 (I H, tt, CH), 2.49(1 H, m, CH-), 1.2-2.0(8H, multi, CH₂) Example 3.

Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l ,4-naphthoquinone (Formula

IV)

10 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l ,4-naphthoquinone

(formula III) obtained in example 2 was suspended in glacial acetic acid (80 ml) and 2.9 gm anhydrous sodium acetate was added to the mixture. The mixture was heated to reflux for 1 hour and then cooled and water was added to the mixture. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 6.5 gm (70% yield) of compound IV.

Example 4.

Preparation of Atovaquone.

6.0 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l ,4-naphthoquinone (formula IV) was suspended in 120 ml methanol and 6.0 gm sodium hydroxide dissolved in 60 ml water was added drop-wise under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5 degrees and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 gm (70% yield) Atovaquone.

Example 5.

A mixture of Silver nitrate 14.17gm (0.0838 moles ), 200 ml water, l OOgm (0.419moles) trans-4-(4-chlorophenyl)cyclohexane carboxylic acid were prepared. To this acetonitrile 500ml was added and under stirring heated to reflux, and 80 gm(0.506moles) 1,4- naphthoquinone was added. 239 gm (1.048 moles) Ammonium persulfate dissolved in 600ml water was added drop-wise to the stirred solution and continued reflux for half an hour. The reaction solution then cooled to 30-32⁰C and extracted with methylene chloride. The organic layer was first washed with water followed by washing with 10% sodium carbonate aqueous solution, further with water till the pH neutral. The organic layer was distilled to eliminate methylene chloride and was stirred in acetonitrile and filtered. The solid obtained was crystallized from acetonitrile to obtain 29.8gm (20.3% yield). M.P. 147- 149⁰C (uncorrected), Example 6.

Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l,4- naphthoquinone (Formula III)

1 17 gm of compound of formula II 2-[4-(4-chlorophenyl)cyclohexyl]-l ,4- naphthoquinone was added to 585 ml glacial acetic acid and to this solution chlorine gas was passed at about 15 degrees. The reaction mass was filtered, washed with glacial acetic acid & water. The product was dried at 30 degree to obtain 120 gm (85% yield) of compound of formula III.

Example 7

Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone (Formula

IV)

1 15.8 gm of 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-l,4- naphthoquinone (formula III) obtained in example 6 was suspended in glacial acetic acid

(926 ml) and 33.77 gm anhydrous sodium acetate was added to the mixture. The mixture was heated to reflux for 1 hour and then cooled and water was added to the mixture. The precipitated product was filtered of and recrystallized from acetonitrile to obtain 94.5 gm

(89.34% yield) of compound IV.

Example 8.

87.3 gm of 2-[4-(4-chlorophenyl)cyclohexyI]-3-chloro- l ,4-naphthoquinone (formula IV) was suspended in 2619 ml methanol and 128 gm potassium hydroxide dissolved in 873 ml water was added drop-wise under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5 degrees and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 71.6 gm (86% yield) Atovaquone.

Example 9

1.0 grams of Atovaquone (Form I) was taken in 35 ml of dichloromethane at room temperature. It was dissolved completely and filtered out any undissolved particles. The solution was then chilled on a nitrogen bath until the dichloromethane solution solidified. The material was lyophilized and dichloromethane was removed completely to obtain novel crystalline form. Yield 1.0 gm. The XRPD, IR spectra & DSC of the sample were recorded and are reproduced in figure 1 to 3.

Example 10

1.0 grams of Atovaquone (Form I) was taken in 35 ml of dichloromethane at room temperature. It was dissolved completely and filtered out of any undissolved particles. The solution was poured on a liquid nitrogen taken in another vessel until the dichloromethane solution solidified. The solid obtained lyophilized and dichloromethane was removed completely to obtain novel crystalline form. Yield 1.0 gm. The XRPD, IR spectra & DSC of the sample were recorded and are reproduced in figure 1 to 3.

Claims

We claim,

1. A compound of Formula III, wherein X is any halogen atom.

Formula

2. A Trans-compound of Formula II.

3. Use of either Compound of Formula III or compound of Formula II in the preparation of Atovaquone.

4. A process for preparation of compounds according to claims 1 or 2 comprises reacting a compound of Formula V and Vl. H

Formula V

Formula Vl

5. A process according to claim 4, wherein the reaction is in presence of a metal nitrate and persulfate compound.

6. A process according to claim 5, wherein the metal nitrate is silver nitrate and persulphate is ammonium persulphate.

7. A process according to claim 4, wherein the Formula II is further reacted with a halogenating agent to obtain compound of Formula III.

8. A process according to claim 7, wherein the halogenating agent is chlorine.

9. A process according to claim 8, wherein the intermediates of Formula III is further reacted to form ^'Atovaquone.

10. The use as claimed in claim 3, wherein the preparation process of atovaquone comprises a. reacting the 1 ,4-naphthoquonone with 4-(4-chlorophenyl)cyclohexane carboxylic acid to obtain the compound of Formula II; b. halogenating compound of formula II to form a dihalo-compound of formula III; c. Subjecting compound of formula III to dehydrohalogenation reaction to obtain a compound of formula IV; and d. Converting the monohalogeno-compound of formula IV into Atovaquone .

1 1. A novel crystalline form of Atovaquone designated as "Form IPCA-ATO".

12. A novel crystalline form as claimed in claim 1 1 , wherein the "Form IPCA-ATO" is characterized by powder X-Ray diffraction pattern containing peaks at 10.05 ±0.2 degrees 2 theta angles.

13. Atovaquone according to claim 12, wherein the powder X-Ray diffraction pattern containing peaks at 6.66, 9.96, 13.1 1 , 18.22, and 23.10 ±0.2 degrees 2Θ angles.

14. Atovaquone according to claim 1 1 further characterized by FT-IR spectra having peaks at 3369, 2935, 1633, 1383, 1338, 1312, 123 land 1053 cm-1

15. Atovaquone according to claim 12, wherein Atovaquone characterized by two endtotherm in a differential scanning calorimetry wherein a first endotherm has an onset temperature in the range of 100-120 ⁰C and second endotherm has an onset temperature in the range of 218 ⁰C

16. A pharmaceutical composition comprising Atovaquone according to claim 10 to 14.

17. Atovaquone prepared by a process comprising a. contacting Atovaquone of any physical form in an organic solvent to obtain a solution; b. subjecting said atovaquone solution to rapid chilling; and c. recovering the Novel Atovaquone from the reaction solution.

18. A pharmaceutical composition comprising the Atovaquone according to claim 17.